This invention relates to novel processes for the preparation and resolution of substituted piperidines and related compounds, as well as to novel intermediates used in such processes.
The substituted piperidines and related compounds that can be prepared by the processes of this invention are substance P receptor antagonists and are therefore useful in treating diseases mediated by an excess of substance P.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named for their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has been shown to be involved in the transmission of pain or migraine [see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, Vol. 25, p. 1009 (1982)], as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract, such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," Edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
The substituted piperidines and related compounds that can be prepared by the methods of this invention are claimed in PCT Patent Application PCT/US 90/00116, filed Jan. 4, 1990, and assigned in common with the present application.